Amidization of pyridine monocarboxylic acids



Patented Apr. 29, 1947 AMIDIZATION F PYRIDINE MONO- CARBOXYLIC ACIDSPaul W. Garbo, Chicago, 111.

N 0 Drawing. Application December 31, 1942, Serial No. 470,817

8 Claims.

This invention relates to the amidization of pyridine monocarboxylicacids and, more particularly, to the manufacture of nicotinamide.

Nicotinamide, the amide of nicotinic acid or pyridine 3-carboxylic acid,is recognized as an important vitamin product which is prescribed inpreference to nicotinic acid because of the latters undesirable sidereactions and physiological effects with certain individuals.

Of the methods of producing nicotinamide known to me, the one proposingthe conversion of ammonium nicotinate to nicotinamide has receivedgreatest attention by the workers in this field because, from atheoretical point of view, one might predict it to be the most directand economical. Basically, this known method involves the formation ofammonium nicotinate, which may be obtained by merely neutralizingnicotinic acid with ammonium hydroxide, and splitting oil with the aidof heat a molecule of water from each molecule of ammonium nicotinate toleave a molecule of nicotinamide. However, in the latter step, sinceammonium nicotinate is not a very stable compound, heat tends todecompose the nicotinate into the original nicotinic acid and ammonia.Accordingly, this method has led to poor yields of nicotinamide andcumbersome separation and recycling techniques for unconverted material.

Considerable improvement in this process was eifected when ammonia gaswas bubbled up through the mass of molten ammonium nicotinate undergoingthe heat treatment. Thus, by bubbling ammonia through molten ammoniumnicotinate at an elevated temperature, e. g., about 160-170 C.conversions as high as about 85% were eifected. That is to say, thefinal reaction mass would show by analysis to comprise about 85%nicotinamide and about 15% nicotinic acid as such or as its salt. Evento reach 85% con version, however, the time of heating and bubblingammonia ran into many hours; higher conversions were possible but thetime of reaction became unreasonably long for usual commercial practice.

Furthermore, from such a reaction mass, the recovery of nicotinamide ina form meeting present stringent specifications for melting point,color, pH, ash, etc., has required cumbersome, time-consuming andexpensive procedures. Also, in view of the high cost of nicotinic acid,it has been necessary to recover, with some difiiculty and expense, theunconverted acid for reuse in a subsequent reaction.

My invention therefore has as a principal object, the provision of amethod for the amidization of pyridine monocarboxylic acids which ischaracterized by its simplicity, the speed of reaction and excellentyield.

A further object is to produce the amides of pyridine monocarboxylicacids without recourse to the use of ammonia gas with its attendantdifi'iculties and disadvantages; in place of ammonia, amidizing agentsare employed which are under normal conditions not gaseous.

Another object of my invention is to facilitate the recovery of theamides in high purity from their reaction masses.

A still further object is to avoid the usual neutralization step forconverting pyridine monocarboxylic acids to the ammonium salts, whichstep is wasteful in the consumption of energy and time which arerequired to remove the water of the neutralization reaction.

Other objects of my invention will become apparent from the disclosurewhich follows.

The invention is based on the discovery that pyridine monocarboxylicacids are converted to the corresponding amides simply by reacting theacids with molten urea. Preferably, to the fused reaction mass is addeda catalyst of the amidization reaction.

According to 4 the invention, the desired pyridine monocarboxylic acidis made to react with the molten urea in any convenient manner such asmixing the comminuted acid and urea and heating the mixture until itbecomes fluid or introducing the acid gradually into a molten mass ofurea. While the reaction starts at about the melting point of urea,viz., 0., higher temperatures are usually employed to promote thereaction. The reaction mass is maintained in the heated fluid stateuntil periodic analyses of the reaction mass indicate that the reactionhas come to a satisfactory stage of completion. Thereupon the producedamide may be separated from the reaction mass comprising, besides theamide, unreacted material, and derivatives and degradation products ofurea, e. g., biuret and cyanuric acid, by any of the known methods.

It appears that in the course of the reaction an appreciable proportionof the urea used is converted to biuret and cyanuric acid. Consequently,while one-half mol of urea with its two NHz groups should theoreticallysuffice to convert one mol of pyridine monocarboxylic acid to the amide,as a practical matter it is advisable to use not less than about one molof urea for each mol of acid. Preferably, about 2 mols of urea are usedwith each mol oi acid. Inasmuch astheureaseemstoactasafluxaswellasareagent for the reaction, large excesses of urea may be employed.However, from an economical point of view, a ratio of about 3 mols ofurea to each mol of acid represents the normal upper limit of ureaconsumption. It should be noted that urea is inexpensive as comparedwith the pyridine monocarboxylic acids; furthermore, such by-products ofthe reaction as biuret and cyanuric are recoverable and saleable. Thusit will be seen that the process of my invention enjoys a very favorableeconomy.

As has been stated, the amidization commences with the melting of theurea, i. e., at about 130 C., but progresses more rapidly as thetemperature is raised. Temperatures in the range of about 150 to about280 C. are generally employed. Preferably, the temperature is maintainedin the range of about 170 to about 230 C. It is understood that thedesirable reaction temperature will differ with each pyridinemonocarboxylic acid that is utilized since its melting point and that ofthe corresponding amide will influence the fluidity of the reactionmass. Thus, for one example, when nicotinic acid is reacted with moltenurea in accordance with my invention to produce nicotinamide which has amelting point of about 131 C., a reaction temperature of about 180 toabout 220 C. is very satisfactory. In general, the temperature is socontrolled that the reaction mass is kept in a fluid condition withoutreaching a stage where excessive foaming occurs.

The amidization is desirably carried out in the presence of suitablecatalysts such as substances consisting of or containing the elementboron or elements of Groups V and VI of the Mendeleefi Periodic Systemand having an atomic number between and 92 inclusive. Representativecatalysts are diammonium phosphate, bismuth sulfate, ammonium vanadate,arsenious oxide and selenium molybdate. Two or more catalysts may beused or the catalyst may be a compound of two or more active elements,e. g., ammonium borotungstate or phosphomolybdate. Preferred catalystsare boric acid and ammonium molybdate. Of course, the catalysts vary intheir activity but the catalytic amount used will generally be in therange of about 0.1 to about 5.0% of the weight of the entire reactionmass.

In some instances, in conducting the amidization it may be helpful toadd a fluidizing medium (a high boiling-point liquid) such asnaphthalene, kerosene, quinoline, nitrobenzene or chloronaphthalene.

As an illustrative example of the process of my invention, there may becited the production of nicotinamide. To 120 parts by weight of urea areadded 123 parts of nicotinic acid mixed with 0.3 part of ammoniummolybdate. The entire mixture is heated and brought to a temperature ofabout 180 to 220 C. In less than minutes the reaction may be consideredcompleted. It is desirable to agitate the reaction mass while thereaction is in progress. The pure nicotinamide product may be recoveredfrom the reaction mass by known methods, e. g., crystallization fromsuitable solvents.

While the amidization process of the invention depends upon the use ofurea, Ihave found that the partial heat-decomposition product of ureamay also be employed. Thus, in the foregoing typical example, a somewhatlarger amount of urea may be heated at 200 C. for about one hour; the

resulting partial heat-decomposition product, chiefly biuret, is thenmade to react with the nicotinic acid. Some ammonia may be evolved inthe course of the reaction and, accordinBly, in some instances it may beadvisable to carry out the operation in a closed system under pressure.

Likewise, instead of the free pyridine monocarboxylic acids, thecorresponding ammonium salts may be converted to amides by heating themin the presence of urea or its partial heat-decomposition product inaccordance with the present invention. One of the aforementionedcatalysts may also be added to promote the conversion. When the ammoniumsalts or mixtures of the ammonium salts and the free acids are utilizedin the amidization process, appreciably less urea is required than whenfree acids alone are used.

In view of the foregoing description, it will be understood that thereaction temperature and time will vary considerably with the particularmaterial, free acid or ammonium salt, that is to be converted, with theselected amidization agent. urea or its partial heat-decompositionproduct. and with the catalyst.

Obviously, many modifications of the basic process of my invention willsuggest themselves to those skilled in the art. For example, theoperation may be made continuous by suspending the comminuted pyridinemonocarboxylic acid in molten urea and pumping the fluid mixture througha heated tube maintained at reaction temperature; the heated tubularreactor is of sufllcient length to discharge a. mass in which theoriginal acid has reached a. satisfactory stage of conversion to theamide.

The term, pyridine monocarboxylic acids, as used in this specificationand the appended claims, comprehends benzopyridine monocarboxylic acids,such as quinaldinic acid.

For the purposes of this invention, biuret may be considered equivalentto the partial heat-decomposition product of urea and, threfore, may beused in its place.

The above description and examples are intended to be illustrative only.Variations of my invention conforming to its spirit are to be consideredwithin the scope of the claims.

What I claim is:

1. The process for the amidization of pyridine monocarboxylic acidcompounds of the class consisting of pyridine monocarboxylic acids andtheir ammonium salts, which comprises reacting a said compound with ureain the proportions of about 2 mols of urea for each mol of said compoundin the presence of a catalyst containing an element selected from groupsV and VI of the Mendeleeii periodic system and having an atomic numberbetween 15 and 92, inclusive, and recovering thus produced amide fromthe resulting reaction mass.

2. The process for the'amidization of pyridine monocarboxylic acidcompounds of the class consisting of pyridine monocarboxylic acids andtheir ammonium salts, which comprises reacting a said compound with ureain the proportions of about 2 mols of urea for each mol of said compoundin the presence of a molybdenum catalyst, and recovering thus producedamide from the resulting reaction mass.

3. The process for the amidization of pyridine monocarboxylic acidcompounds of the class consisting of pyridine monocarboxylic acids andtheir ammonium salts, which comprises reacting a said compound with ureaat a temperature in the range of about to about 280 C. in the presenceof a molybdenum catalyst, and recovering thus produced amide from theresulting reaction mass.

4. The process for the production oi. nicotinamide, which comprisesreacting a nicotinic acid compound of the class consisting of nicotinicacid and its ammonium salt with urea in the proportions of about 2 molsof urea for each mol of said compound in the presence of a catalystcontaining an element selected from groups V and VI of the Mendeleeffperiodic system and having an atomic number between 15 and 92,inclusive, maintaining the reaction at a temperature in the range ofabout 150 to about 280 C., and recovering thus produced nicotinamidefromthe resulting reaction-mass.

5. The process for the production of nicotinamide, which comprisesreacting a nicotinic acid compound of the class consisting of nicotinicacid and its ammonium salt with urea in the presence of a molybdenumcatalyst, maintaining the reaction at a temperature in the range ofabout 150 to about 280 0., and recovering thus produced nicotinamidefrom the resulting reaction mass.

6. The process for the production of nicotinamide, which comprisesreacting a nicotinic acid compound of the class consisting of nicotinicacid and its ammonium salt with urea in the proportions of about 2 molsof urea for each mol of said compound in the presence of a molybdenumcatalyst, maintaining the reaction at a temperature in the range ofabout 150 to about 280 C., and recovering thus producednicotinamide-from the resulting reaction mass.

with urea in the proportions of about 2 mols of urea for each mol ofnicotinic acid in thepresence of ammonium molybdate as catalyst,maintaining the reaction at a temperature in the range of about to about230 0., and recovering thus produced nicotinamide from the resultingreaction mass.

PAUL W. GARBO.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,314,483 Hultquist Mar. 23, 19431,989,968 Bruson Feb. 5, 1935 FOREIGN PATENTS Number Country Date418,247 British 1934

